Central nervous system immunological network
The central nervous system (CNS) has relative immunological privilege compared with the peripheral nervous system (PNS) and most other parts of the body. The reasons for this are as follows:
· The blood–brain barrier (BBB) normally prevents most lymphocytes, macrophages and antibodies from entering the CNS (see Chapters 5 and 13).
• It has a very poorly developed lymphatic drainage system.
• There is only low level expression of major histocompatibility complex (MHC) antigens.
However, breakdown of the BBB can greatly alter this situation. In the resting state some activated T lymphocytes are able to cross the BBB and circulate within the CNS. In addition, MHC expression is confined to only a few cells although the situation is different in the inflamed state. Thus, once triggered, an immune response can be amplified and propagated by the secretion of cytokines and induced MHC expression, with the opening up of the BBB. In these circumstances the microglia are thought to be important as the antigen-presenting cells and their interaction with T-helper lymphocytes is then pivotal in generating a full-blown immunological reaction.
Recently there has been great interest in the possible role of inflammation in neurodegenerative disorders of the CNS and the extent to which this is seen simply as a reaction to the cell degeneration or as a primary contributory factor in causing the loss of these cells (see Chapter 60).
Clinical disorders of the central nervous system with an immunological basis Multiple sclerosis
Multiple sclerosis is a common neurological disorder in which the patient characteristically presents with episodes of neurological dysfunction secondary to inflammatory lesions within the CNS. Pathologically, these lesions represent small areas of demyelination secondary to an underlying inflammatory (mainly T cell) infiltrate the trigger and target for which is not clear. The lesions often resolve with remyelination and clinical recovery, although with time a permanent loss of myelin ensues with secondary axonal loss and the development of fixed disabilities.
To date the most successful symptomatic therapy is high-dose steroids which hastens recovery from acute relapses but does not alter the long-term disease process. Of late, though, a number of more aggressive immunotherapies with drugs that target the T cells seem to be more effective, especially if given early on in the course of the disease before there has been significant axonal loss.
Acute disseminated encephalomyelitis
This is a rare inflammatory demyelinating disease of the CNS that occurs as a complication of a number of infections and vaccinations (e.g. measles and rabies vaccination). It is a monophasic illness (unlike multiple sclerosis) characterized by widespread disseminated lesions throughout the CNS that pathologically consists of an intense perivascular infiltrate of lymphocytes and macrophages with demyelination. In some cases it is fatal. This condition resembles experimental allergic encephalomyelitis, which is a well-characterized T cell-mediated disorder against a component of myelin (probably myelin basic protein) induced by inoculating animals with a combination of sterile brain tissue and adjuvants. This disorder is often used experimentally to model multiple sclerosis.
Other immunological diseases
A number of other diseases with an immunological basis can affect the CNS and these include those diseases that primarily affect blood vessels (the vasculitides).
In addition, there is a rare group of disorders in which there is CNS dysfunction as a remote effect of a cancer, paraneoplastic syndromes. In these conditions antibodies to components of the CNS are generated, presumably triggered by the tumour, which then lead to neuronal cell death and the development of a neurological syndrome, e.g. anti-Purkinje cell antibodies cause a profound cerebellar syndrome by the immunological removal of this cell type in the cerebellum. The exact mechanism by which these antibodies exert their effect is not known as antibodies normally do not cross the BBB, but pathologically there is often evidence of a lymphocytic infiltrate in the affected structure which implies that the antibody is capable of inducing an immune-mediated process of neuronal loss.
Finally it has been shown that a number of CNS disorders are caused by antibodies to specific ion channels or receptors e.g. anti-K+ channel antibodies causing a limbic encephalitis or anti- N-methyl-D-aspartate (NMDA) receptor antibodies causing psychoses, a movement disorder and encephalopathy – many of which are not associated with any underlying malignancy but are primary immunological disorders. Indeed there is a growing interest in the possibility that some patients with psychiatric disorders may have an autoimmune disease targeting a receptor/ion channel.
Clinical disorders of the peripheral nervous system with an immunological basis
The PNS has fewer of the protective features of the CNS so it is more susceptible to conventional immune-mediated diseases.
· The peripheral nerve is affected by a number of immunological processes, including Guillain–Barré syndrome. In this condition there is often a preceding illness (e.g. Campylobacter jejuni or cytomegalovirus infection) that induces an immune response which then cross-reacts with components in the peripheral nerve (e.g. certain gangliosides). This then induces focal demyelination in the peripheral nerve, which prevents it from conducting action potentials normally (see Chapter 17). In time the patient usually recovers, although they may require immunotherapy with either plasma exchange or intravenous immunoglobulin. A similar condition is seen in some diseases where abnormal amounts of a component of antibodies are produced (the paraproteinaemias).
· The neuromuscular junction can be affected by immunological processes as occurs in myasthenia gravis and the Lambert–Eaton myasthenic syndrome (see Chapter 16).
· Muscles can be involved in inflammatory processes. The most common form of this is polymyositis, which is a T cell-mediated condition associated with proximal weakness and pain. In contrast, dermatomyositis is a B cell-mediated disease centred on blood vessels, which causes a painful proximal muscle weakness in association with a florid skin rash. This latter condition can represent a paraneoplastic syndrome in more elderly patients with tumours in the lung, breast, colon or ovary.